The pathophysiology of thalassemia major is best understood by going and getting yourself

a beer (or politically correct beverage), watching a little TV, doing one or two other chores to
postpone the inevitable, and then sitting down to study the next diagram.

While studying the illustration, consider the following observations concerning

thalassemia:

1. Since there is a decrease in the synthesis of chains, there is a net decreased synthesis
of Hb A. With less Hb A available to fill the red cells, the result is microcytic anemia.
Whereas in iron deficiency microcytosis occurs because there is not enough heme, in
thalassemia the same thing occurs because there is not enough globin.

2. Since the body cannot make enough chains, it makes a feeble attempt to compensate
by trying to churn out chains. The result is increased Hb A , which can be measured
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easily and inexpensively by column chromatography. This is a pretty specific test for
the diagnosis of thalassemia. Pitfall: both and chains are decreased in
thalassemia, which is not rare and presents like thalassemia, except that the Hb A is 2

not elevated. You would expect this since Hb A contains chains).

2

3. In some cases of thalassemia, there is attempt at compensation by maintaining some

production of Hb F. This has some pathophysiologic consequences (as shown above)
and also provides a laboratory marker to assist in diagnosis. Retention of Hb F
production is not as common as increased rbc Hb A content.
2

4. In severe forms of thalassemia, the anemia due to failure to make adequate amounts
of Hb A is compounded by the hemolysis, ineffective erythropoiesis, and
extramedullary hematopoiesis brought on by precipitation of tetramers (which are
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unstable). In classic Cooley's anemia, the ineffective erythropoiesis dominates the

clinical picture by producing tremendous expansion of the marrow space, manifested
by the so-called "tower skull" with an x-ray showing innumerable vertical bony striae
between the inner and outer tables of the calvarium. This radiographic feature is
fancifully called the "hair-on-end appearance" by radiologists, and the "guy-who-
accidentally-sat-on-a-Van-de-Graaff-generator appearance" by those wacky
 electrical engineers. Extramedullary hematopoiesis and hemolysis causes
splenomegaly, which produces hypersplenism, and more hemolysis.

5. The high turnover state caused by the tremendous erythroproliferative activity causes
wastage of folate and may produce a complicating megaloblastic anemia. Another
effect of the high turnover state is hyperuricemia (due to catabolism of the purine
content of cellular DNA).

6. Classically in thalassemia major, the treatment is the cause of death. The children are
maintained by transfusions until about age ten years, at which time they start to show
symptoms of excess iron loading. This happens because the transfusion bypasses the
body's normal gastrointestinal mechanism of iron intake and excretion. The iron is
poured into the bloodstream directly; the body cannot excrete it fast enough. First
iron (as hemosiderin) fills the cytoplasm of the RES phagocytes and then starts to be
deposited in the parenchymal cells of just about every organ of the body. The
pancreas, liver, myocardium, adrenals, and gonads are among the organs most
sensitive to iron toxicity. The clincial result is diabetes mellitus, hepatic cirrhosis,
congestive heart failure, adrenal insufficiency, and failure to undergo puberty.
Death used to occur in the second or third decade of life, the most common immediate
cause being complications of heart failure. Nowadays, thal major patients live longer
because of advances in chelation therapy. To achieve such longevity, they must submit
to daily subcutaneous injections of the parenteral chelating agent, deferoxamine.
These injections are given by pump, usually overnight, and last 9 to 12 hours each.
An oral chelating drug in presently under development in Europe.